PCTR1 improves pulmonary edema fluid clearance through activating the sodium channel and lymphatic drainage in lipopolysaccharide‐induced ARDS

Abstract

Acute respiratory distress syndrome (ARDS) is a lethal clinical syndrome characterized by damage of the epithelial barriers and accumulation of pulmonary edema fluid. Protectin conjugates in tissue regeneration 1 (PCTR1), an endogenously produced lipid mediator, are believed to exert anti‐inflammatory and pro‐resolution effects. PCTR1 (1 µg/kg) was injected at 8 hr after lipopolysaccharide (LPS; 14 mg/kg) administration, and the rate of pulmonary fluid clearance was measured in live rats at 1 hr after PCTR1 treatment. The primary type II alveolar epithelial cells were cultured with PCTR1 (10 nmol/ml) and LPS (1 μg/ml) for 8 hr. PCTR1 effectively improved pulmonary fluid clearance and ameliorated morphological damage and reduced inflammation of lung tissue, as well as improved the survival rate in the LPS‐induced acute lung injury (ALI) model. Moreover, PCTR1 markedly increased sodium channel expression as well as Na, K‐ATPase expression and activity in vivo and in vitro. In addition, PCTR1i also upregulated the expression of LYVE‐1 in vivo. Besides that, BOC‐2, HK7, and LY294002 blocked the promoted effect of PCTR1 on pulmonary fluid clearance. Taken together, PCTR1 upregulates sodium channels' expression via activating the ALX/cAMP/P‐Akt/Nedd4‐2 pathway and increases Na, K‐ATPase expression and activity to promote alveolar fluid clearance. Moreover, PCTR1 also promotes the expression of LYVE‐1 to recover the lymphatic drainage resulting in the increase of lung interstitial fluid clearance. In summary, these results highlight a novel systematic mechanism for PCTR1 in pulmonary edema fluid clearance after ALI/ARDS, suggesting its potential role in a therapeutic approach for ALI/ARDS.

Pulmonary Edema in COVID-19 Patients: Mechanisms and Treatment Potential

“…Since pulmonary edema can be promoted by decreased expression of alveolar Na-K-ATPase ( Woods et al, 2015 ), drugs or compounds which activate the sodium channel and Na-K-ATPase may be putative therapeutics. Studies have shown that MCTR1 ( Han et al, 2020 ), PCTR1 ( Zhang et al, 2020 ) and protectin DX ( Zhuo et al, 2018 ), endogenously produced lipid mediators, can effectively improve PFC, ameliorate morphological damage, reduce lung inflammation, and increase sodium channel and Na-K-ATPase expression and activity in vivo and in vitro in lipopolysaccharide (LPS)-induced ARDS rats model. Resolving D1 ( Wang et al, 2014 ), generated from ω-3 fatty docosahexaenoic acids, and ursodeoxycholic acid ( Niu et al, 2019 ) can stimulate AFC and Na-K-ATPase in LPS-induced pulmonary edema via alveolar epithelial sodium channel and ALX/cAMP/PI3K pathway, respectively.…”

Protectin Conjugates in Tissue Regeneration 1 Restores Lipopolysaccharide-Induced Pulmonary Endothelial Glycocalyx Loss via ALX/SIRT1/NF-kappa B Axis

“…Moreover, PCTR1 generation in peritoneal lavage is decreased in vagotomized mice, suggesting that PCTR1 is controlled by local vagal to improve in ammation resolution [13] . Our previous studies demonstrated that PCTR1 reduced LPS-induced in ammation in mice via regulating linoleic acid metabolism, and improved pulmonary edema uid clearance by activating the sodium channel and lymphatic drainage in LPS-triggered rat model [17,18] . Similarly, we also observed that PCTR1 improved lung function and lung vascular leakage after LPS challenge in mice.…”

<p>Lymphatic Flow: A Potential Target in Sepsis-Associated Acute Lung Injury</p>

“…As a result, it was shown that one of the fundamental causes of sepsis is the inability to resolve inflammation since promoting the resolution of inflammation in mice with sepsis effectively reduced mortality. 35 , 36 Additionally, lymphatic vessels could effectively transfer inflammatory cells and factors away from tissues and into blood circulation, thereby reducing damage, and promoting the resolution of inflammation. Furthermore, existing research on rat mesentery suggests that Lipopolysaccharide (LPS) modulate neutrophil recruitment and macrophage polarization on lymphatic vessel, thereby impairing lymphatic function.…”

“…Previous studies from our research group also showed that SPMs could reduce mortality in rats with sepsis and promote the elimination of pulmonary edema fluid as well as inflammatory cells. 36 , 69 Therefore, more studies are needed to establish the therapeutic efficacy of SPMs in promoting the repair and the generation of lymphatics, which will eventually accelerate the resolution of inflammation during sepsis.…”